Ophthalmic and aural compositions containing diclofenac potassium

ABSTRACT

The present invention describes an ophthalmic composition comprising diclofenac potassium, the use of said composition as a medicament for treating inflammatory conditions of the eye, for treating glaucoma or for treating ear inflammatory and/or painful conditions (otitis); as well as the use of diclofenac potassium in the preparation of a pharmaceutical composition for treating any inflammatory condition of the eye, for treating glaucoma or for treating ear inflammatory and/or painful conditions (otitis).

This is a divisional of application Ser. No. 08/809,434, filed Aug. 27,1997, now U.S. Pat. No. 5,891,913 which is a continuation ofPCT/EP95/03844, filed Sep. 28, 1995.

The present invention describes an ophthalmic composition comprisingdiclofenac potassium, the use of said composition as a medicament fortreating inflammatory conditions of the eye, for treating glaucoma orfor treating ear inflammatory and/or painful conditions (otitis); aswell as the use of diclofenac potassium in the preparation of apharmaceutical composition for treating any inflammatory condition ofthe eye, for treating glaucoma or for treating ear inflammatory and/orpainful conditions (otitis).

Hitherto, predominantly corticosteroids have been used for the treatmentof relatively severe acute or chronically recurrent inflammatorysymptoms in the eye. The immunosuppressant action of these substances,however, conceals the risk of a deterioration in the clinical picture asa result of a bacterial or viral infection. Therefore, considerableefforts are still made, to develop potent non-steroidalanti-inflammatory agents and to introduce them into ophthalmologicaltherapy.

EP 242 328 describes for example a medicament for the treatment ofinflammations of the eye, which medicament comprises sodium2-[(2,6-dichlorophenyl)amino]-phenyl acetate, known as diclofenacsodium.

Diclofenac-potassium, is chemically described as potassium2-[(2,6-dichlorophenyl)amino]-phenyl acetate. It is known as anon-steroidal anti-inflammatory drug (NSAID). A Norwegian publication,Cephalalgia 13, 117-123(1993), describes for example the use ofdiclofenac potassium in the acute treatment of migraine.

A stabilized aqueous solution of pharmaceutically acceptable salts of2-[(2,6-dichlorophenyl)amino]-phenyl acetic acid for ophthalmic use isdisclosed in U.S. Pat. No. 4,960,799. Diclofenac potassium is notspecifically disclosed in said application. Accordingly, all claims andworking examples of said application disclose either diclofenac sodiumor its free acid as a pharmaceutically active ingredient. Hence, saidapplication is clearly directed towards the provision of a stableaqueous solution of a pharmaceutically acceptable salt of2-[(2,6-dichlorophenyl)amino]-phenyl acetic acid containing an effectiveamount of a pharmaceutically acceptable salt of ethylenediaminetetraacetic acid.

Surprisingly it was found, that the potassium salt of2-[(2,6-dichlorophenyl)amino]-phenyl acetic acid, diclofenac potassium,is especially suitable to treat inflammatory ocular processes ingeneral. It has been demonstrated that for example the ocularpenetration of diclofenac potassium is much superior in comparison tothe corresponding diclofenac sodium. In addition to said advantage,pharmacological studies show a much better topical tolerance, e.g.ocular tolerance, and efficacy of diclofenac potassium in comparison todiclofenac sodium and also a surprisingly short onset of action as wella long lasting duration of action e.g. in the eye.

Therefore the present invention relates to an ophthalmic composition fortreating inflammatory ocular conditions, for treating glaucoma or fortreating ear inflammatory and/or painful conditions (otitis), whichcomposition comprises a therapeutically effective amount of diclofenacpotassium and a carrier.

The present invention relates also to an ophthalmic composition fortreating inflammatory conditions of the eye, which composition comprisesa therapeutically effective amount of diclofenac potassium and acarrier.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier and a stabilizer.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier and a solubilizer.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier, a stabilizer and a solubilizer.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier, a solubilizer, a stabilizer and a complexing agent.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier, a solubilizer, a stabilizer, a complexing agent and a tonicityenhancing agent.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier, a solubilizer, a stabilizer, a complexing agent, a tonicityenhancing agent and a buffer.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier, a solubilizer, a stabilizer, a complexing agent, a tonicityenhancing agent, a buffer and a preservative.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium anda carrier, and is further comprising one or more of the excipientsselected from the group consisting of buffers, complexing agents,tonicity enhancing agents, preservatives and fillers.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier and a stabilizer, and is further comprising one or more of theexcipients selected from the group consisting of buffers, complexingagents, tonicity enhancing agents, preservatives and fillers.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier and a solubilizer, and is further comprising one or more of theexcipients selected from the group consisting of buffers, complexingagents, tonicity enhancing agents, preservatives and fillers.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier, a solubilizer and a stabilizer, and is further comprising oneor more of the excipients selected from the group consisting of buffers,complexing agents, tonicity enhancing agents, preservatives and fillers.

Another aspect of the present invention is the use of diclofenacpotassium and a carrier in the preparation of a pharmaceuticalcomposition for treating inflammatory ocular conditions, for treatingglaucoma or for treating ear inflammatory and/or painful conditions(otitis).

The present invention relates also to the use of diclofenac potassiumand a carrier in the preparation of a pharmaceutical composition fortreating inflammatory ocular processes.

The present invention relates also to the use of diclofenac potassium, acarrier and a stabilizer in the preparation of a pharmaceuticalcomposition for treating inflammatory ocular conditions, for treatingglaucoma or for treating ear inflammatory and/or painful conditions(otitis).

The present invention relates also to the use of diclofenac potassium, acarrier, a stabilizer and a solubilizer in the preparation of apharmaceutical composition for treating inflammatory ocular conditions,for treating glaucoma or for treating ear inflammatory and/or painfulconditions (otitis).

Still another aspect of the present invention is a method of treatinginflammatory ocular conditions, which method comprises administeringtopically to the eye of a patient requiring such treatment atherapeutically effective amount of an ophthalmic composition comprisingdiclofenac potassium and a carrier.

The present invention relates also to a method of treating inflammatoryocular conditions, which method comprises administering topically to theeye of a patient requiring such treatment a therapeutically effectiveamount of an ophthalmic composition comprising diclofenac potassium, acarrier and a stabilizer.

The present invention relates also to a method of treating inflammatoryocular conditions, which method comprises administering topically to theeye of a patient requiring such treatment a therapeutically effectiveamount of an ophthalmic composition comprising diclofenac potassium, acarrier, a stabilizer and a solubilizer.

In the present invention, treating inflammatory ocular conditions means,treating all ophthalmological diseases involving inflammatory processes,whatever the causes are. Examples for such causes are e.g. allergic ornon-allergic inflammation, immune and non-immune processes, acute orchronic disease. Examples for such treatments of ocular inflammationsare the inhibition of miosis during ocular surgery, prevention ortreatment of ocular pain during these processes or consequent uponsurgery, inhibition of photophobia, treatment of uveitis or ocularinflammation of any cause and the like. Post operative inflammations arefor example, of the type associated with cataract removal orphoto-refractive surgery or incisional refractive surgery,trabeculectomy and combined procedures thereof, painful eye-conditions(including photophobia and post-operative pain), pain associated withtrauma or foreign bodies, prevention and treatment of macular edema(idiopathic or associated with surgical interventions or diabetes) andinhibition of miosis.

According to the present invention an ophthalmic composition may also beused for treating glaucoma in connection with non-inflammatory inducedelevated intraocular pressure associated with administered or endogenousglucocorticoids.

According to the present invention an ophthalmic composition may also beused for treating ear inflammatory and/or painful conditions (otitis).

According to the present invention an ophthalmic composition maypreferably be used for treating inflammatory ocular conditions.

According to the invention an ophthalmic composition is advantageouslyapplied topically to the eye, especially in the form of a solution, asuspension, an ointment, a gel or a solid insert. Such compositionscomprise the active ingredient, for example, in a range of fromapproximately 0.000001 to approximately 5.0% by weight, preferably fromapproximately 0.001 to approximately 1.0% by weight, or more preferablyin the range of from approximately 0.01 to approximately 0.5% by weightand most preferably in the range of from 0.025 to 0.1% by weight. Thedose of the active ingredient may depend on various factors, such asmode of administration, requirement, age and/or individual condition.Analogously an above ophthalmic composition may be also topicallyapplied to an ear.

There are used for a corresponding ophthalmic composition customarypharmaceutically acceptable excipients and additives known to the personskilled in the art, for example those of the type mentioned below,especially carriers, stabilizers, solubilizers, tonicity enhancingagents, buffer substances, preservatives, thickeners, complexing agentsand other excipients. Examples of such additives and excipients can befound in U.S. Pat. Nos. 5,134,124 and 4,906,613. Such compositions areprepared in a manner known per se, for example by mixing the activeingredient with the corresponding excipients and/or additives to formcorresponding ophthalmic compositions. The active ingredient ispreferably administered in the form of eye drops, the active ingredientbeing conventionally dissolved, for example, in a carrier. The solutionis, where appropriate, adjusted and/or buffered to the desired pH and,where appropriate, a stabilizer, a solubilizer or a tonicity enhancingagent is added. Where appropriate, preservatives and/or other excipientsare added to an ophthalmic composition.

Carriers used in accordance to the present invention are typicallysuitable for topical or general administration, and are for examplewater, mixtures of water and water-miscible solvents, such as C₁ - to C₇-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% byweight hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose,polyvinyl-pyrrolidone and other non-toxic water-soluble polymers forophthalmic uses, such as, for example, cellulose derivatives, such asmethylcellulose, alkali metal salts of carboxymethylcellulose,hydroxymethylcellulose, hydroxyethylcellulose,methylhydroxypropylcellulose and hydroxypropylcellulose, acrylates ormethacrylates, such as salts of polyacrylic acid or ethyl acrylate,polyacrylamides, natural products, such as gelatin, alginates, pectins,tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia,starch derivatives, such as starch acetate and hydroxypropyl starch, andalso other synthetic products, such as polyvinyl alcohol,polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide,preferably cross-linked polyacrylic acid, such as neutral Carbopol, ormixtures of those polymers. Preferred carriers are water, cellulosederivatives, such as methylcellulose, alkali metal salts ofcarboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,methylhydroxypropylcellulose and hydroxypropylcellulose, neutralCarbopol, or mixtures thereof. The concentration of the carrier is, forexample, from 1 to 100 000 times the concentration of the activeingredient.

The solubilizers used for an ophthalmic composition of the presentinvention are, for example, tyloxapol, fatty acid glycerol poly-loweralkylene glycol esters, fatty acid poly-lower alkylene glycol esters,polyethylene glycols, glycerol ethers or mixtures of those compounds. Aspecific example of an especially preferred solubilizer is a reactionproduct of castor oil and ethylene oxide, for example the commercialproducts Cremophor EL® or Cremophor RH 40®. Reaction products of castoroil and ethylene oxide have proved to be particularly good solubilizersthat are tolerated extremely well by the eye. Another preferredsolubilizer is tyloxapol. The concentration used depends especially onthe concentration of the active ingredient. The amount added istypically sufficient to solubilize the active ingredient. For example,the concentration of the solubilizer is from 0.1 to 5000 times theconcentration of the active ingredient.

According to the present invention lower alkylene means linear orbranched alkylene with up to and including 7 C-atoms. Examples aremethylene, ethylene, 1,3-propylene, 1,2-propylene, 1,5-pentylene,2,5-hexylene or 1,7-heptylene.

Lower alkylene is preferably linear or branched alkylene with up to andincluding 4 C-atoms.

Examples of buffer substances are acetate, ascorbate, borate, hydrogencarbonate/carbonate, citrate, gluconate, lactate, phosphate, propionateand TRIS (tromethamine) buffers. Tromethamine and borate buffer arepreferred buffers. The amount of buffer substance added is, for example,that necessary to ensure and maintain a physiologically tolerable pHrange. The pH range is typically in the range of from 5 to 9, preferablyfrom 6 to 8.2 and more preferably from 6.8 to 8.1.

Tonicity enhancing agents are, for example, ionic compounds, such asalkali metal or alkaline earth metal halides, such as, for example,CaCl₂, KBr, KCl, LiCl, Nal, NaBr or NaCl, or boric acid. Non-ionictonicity enhancing agents are, for example, urea, glycerol, sorbitol,mannitol, propylene glycol, or dextrose. For example, sufficienttonicity enhancing agent is added to impart to the ready-for-useophthalmic composition an osmolality of approximately from 50 to 1000mOsmol, preferred from 100 to 400 mOsmol, more preferred from 200 to 400mOsmol and even more preferred from 280 to 350 mOsmol.

Examples of preservatives are quaternary ammonium salts, such ascetrimide, benzalkonium chloride or benzoxonium chloride, alkyl-mercurysalts of thiosalicylic acid, such as, for example, thiomersal,phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate,parabens, such as, for example, methylparaben or propylparaben,alcohols, such as, for example, chlorobutanol, benzyl alcohol or phenylethanol, guanidine derivatives, such as, for example, chlorohexidine orpolyhexamethylene biguanide, or sorbic acid. Preferred preservatives arecetrimide, benzalkonium chloride, benzoxonium chloride and parabens.Where appropriate, a sufficient amount of preservative is added to theophthalmic composition to ensure protection against secondarycontaminations during use caused by bacteria and fungi.

The ophthalmic compositions may comprise further non-toxic excipients,such as, for example, emulsifiers, wetting agents or fillers, such as,for example, the polyethylene glycols designated 200, 300, 400 and 600,or Carbowax designated 1000, 1500, 4000, 6000 and 10 000. Otherexcipients that may be used if desired are listed below but they are notintended to limit in any way the scope of the possible excipients. Theyare especially complexing agents, such as disodium-EDTA or EDTA,antioxidants, such as ascorbic acid, acetylcysteine, cysteine, sodiumhydrogen sulfite, butyl-hydroxyanisole, butyl-hydroxy-toluene orα-tocopherol acetate; stabilizers, such as a cyclodextrin, thiourea,thiosorbitol, sodium dioctyl sulfosuccinate or monothioglycerol; orother excipients, such as, for example, lauric acid sorbitol ester,triethanol amine oleate or palmitic acid ester. Preferred exipients arecomplexing agents, such as disodium-EDTA and stabilizers, such as acyclodextrin. The amount and type of excipient added is in accordancewith the particular requirements and is generally in the range of fromapproximately 0.0001 to approximately 90% by weight.

A cyclodextrin as is referred to within the present invention is eitheran α-, β- or γ-cyclodextrin itself, a derivative thereof, e.g. apartially etherified derivative as e.g. a hydroxyalkyl ether or amixture thereof. Examples of cyclodextrin derivatives are alkylated,hydroxyalkylated, carboxyalkylated or alkyloxycarbonyl-alkylated α-, β-or γ-cyclodextrins. Other typical examples are carbohydrate derivativesof cyclodextrins such as mono- or diglycosyl-α-, β- or γ-cyclodextrin,mono- or dimaltosyl-α-, β- or γ-cyclodextrin or panosyl-cyclodextrin.Another parameter which describes the substitution pattern of acyclodextrin derivative is the degree of substitution (d.s.). Acyclodextrin is composed of several glucose units which have three freehydroxy groups per glucose. Accordingly the d.s. may vary from 0.125 upto 3. In the latter case all free (γ-cyclodextrin has 24) hydroxy groupsmay be substituted, while in the former case only 1 may be substituted.Preferably the d.s. may vary from 0.125 to 1.5 and more preferably from0.125 to 0.5.

Preferred cyclodextrins are β- and γ-cyclodextrin, derivatives andmixtures thereof.

Strongly preferred cyclodextrins are hydroxypropyl-β-cyclodextrin,hydroxypropyl-γ-cyclodextrin, dimethyl-β-cyclodextrin anddimethyl-γ-cyclodextrin.

The amount of a cyclodextrin used in accordance with the presentinvention may preferably range from 0.01-20% by weight, more preferablyfrom 0.1-15% by weight and even more preferably from 1-10% by weight.

The present invention relates also to an ophthalmic composition, whichcomprises a therapeutically effective amount of diclofenac potassium, acarrier, a solubilizer and another therapeutically effectivepharmaceutical agent which may be, for example, an antibiotic, anantiallergic, an anesthetic, another antiphlogistic, a corticosteroide,an agent suitable for lowering intra-ocular pressure, or another drug.

Several animal models are used for the demonstration of the claimedtherapeutic efficacy of the ophthalmic compositions comprisingdiclofenac potassium. In each animal model several ophthalmic referencedrugs are administered for comparison.

In a first animal model, the ocular distribution and lens penetration ofdiclofenac potassium and diclofenac sodium is determined after multipletopical ocular administration of a corresponding eye drop composition.Hence 14C labelled eye drop material is topically administered to theeyes of chinchilla pigmented rabbits (5 instillations, 50 μl each,within 20 minutes). At regular intervals post-instillation (0.5, 1.5,2.0 hours), the animals are sacrificed and both eyes are removed. Saideyes are microdissected and the ocular distribution of the radioactivityis measured by a standard scintillation beta counting method. Thehighest concentrations are found in the cornea, and in descending orderin the aqueous humor, in the iris ciliary body and in the vitreous.According to this experimental setup, the diclofenac potassium treatedanimals clearly displayed higher levels of radioactivity in theaforementioned areas than the diclofenac sodium treated animals.

Another animal model is used for the comparison of the ocularanti-inflammatory efficacy of diclofenac potassium in comparison todiclofenac sodium, which model is the arachidonic acid induced uveitisin pigmented rabbits. Repeated instillations of arachidonic acid intothe eye of rabbits induce an ocular inflammation, which inflammationsignificantly increases the flare level in the anterior chamber ofrabbits. A laser cell flare meter (LCFM) is used for the quantificationof said flare levels. This method is described by e.g. M. Kuchle et al.,Ophthalmologe 91, 219(1994), and is a non-invasive method. It has beendemonstrated, that the flare determination by LCFM reflects the amountsof proteins comprised in the aqueous humor. These proteins are commonlyused as markers in assessing the degree of an inflammation. For thenon-invasive evaluation of the efficacy of an anti-inflammatory drug,said drugs are administered by using two instillations one hour and 45minutes before the induction of an arachidonic acid induced inflammationas described above. A control group of animals is treated with a singleinstillation of non-preserved saline (Unilarm®). The inflammationprocess is monitored during 6 hours post-inflammation by the abovedescribed LCFM measurements.

In a further animal model the ocular anti-inflammatory efficacy ofdiclofenac potassium is determined with a traumatic uveitis model.Uveitis is induced in said model by an argon laser iris photocoagulationin pigmented rabbits. Said iris photocoagulation is induced by 500 μmargon laser burns (power 750 mW, duration 0.1 sec). The inflammatoryprocesses resulting therefrom are measured every 30 minutes after thelaser induced photo-coagulation, by using the laser cell flare meter(LCFM) technique. For the evaluation of the efficacy of ananti-inflammatory drug, said drugs are again administered by twoinstillations, one hour and 45 minutes prior to the induction of aninflammation as described above. A control group of animals is treatedwith instillations of non-preserved saline (Unilarm®). Again theinflammation process is monitored during 6 hours.

In addition to the non invasive LCFM evaluation of the above mentionedanimal model, an invasive evaluation is carried out. Therefore therabbits are sacrificed one hour and in regular intervals after whichsaid eyes have been subjected to the traumatic uveitis byphotocoagulation, and the aqueous humor of said rabbit eyes is sampled.The aqueous protein levels, cell counts and prostaglandins (PGE2, PGD2,6-keto PGF1α) which represent the degree of an inflammation arebiochemically investigated and quantified.

Another animal model is used for the induction of a traumatic uveitis.It is the induction of a uveitis by the paracentesis of the anteriorchamber of the rabbit eye. In analogy to the previously described laserinduced uveitis model, drugs to be tested, are again administered priorto the paracentesis challenge. In this animal model, the animals areagain sacrificed at regular intervals, and the inflammatory process isinvestigated by sampling the aqueous humor of the challenged rabbiteyes. The aqueous protein levels are again analyzed, quantified and thencorrelated with the degree of an inflammation.

In all the aforementioned animal models, there is clear evidence thatanimals which are treated with diclofenac potassium benefit from abetter efficacy compared to the animals treated with diclofenac sodium.

Typical experimental procedures which illustrate the present invention,but are not intended to limit it in any way, are described below.

EXAMPLE 1 Formulation of diclofenac potassium eye drops (0.1%)

    ______________________________________                                        diclofenac potassium    1.00   mg/ml                                          thiomersal              0.04   mg/ml                                          boric acid              19.0   mg/ml                                          cremophor EL ® (polyoxyl 35 castor oil)                                                           50.0   mg/ml                                          tromethamine            6.0    mg/ml                                          deion. water ad.        1.0    ml                                             ______________________________________                                    

EXAMPLE 2 Formulation of diclofenac potassium eye drops (0.05%)

    ______________________________________                                        diclofenac potassium 0.50   mg/ml                                             benzalkonium chloride                                                                              0.05   mg/ml                                             disodium edetate     1.0    mg/ml                                             tyloxapol            1.0    mg/ml                                             γ-cyclodextrin 20.0   mg/ml                                             tromethamine         1.0    mg/ml                                             hydrochloric acid 10%                                                                              1.3    mg/ml                                             sorbitol             46.0   mg/ml                                             deion. water ad.     1.00   ml                                                ______________________________________                                    

EXAMPLE 3 Formulation of non-preserved uni-dose diclofenac potassium eyedrops (0.1%)

    ______________________________________                                        diclofenac potassium  1.00   mg/ml                                            disodium edetate      1.0    mg/ml                                            tyloxapol             0.1    mg/ml                                            dimethyl-β-cyclodextrin                                                                        40.0   mg/ml                                            tromethamine          1.0    mg/ml                                            hydrochloric acid 10% 1.3    mg/ml                                            sorbitol              41.0   mg/ml                                            deion. water ad.      1.00   ml                                               ______________________________________                                    

EXAMPLE 4 Formulation of oily eye drops

    ______________________________________                                        diclofenac potassium      0.50   mg/ml                                        benzalkonium chloride     0.1    mg/ml                                        cremophor RH 40 ®, (polyoxyl 40 hydrogenated castor                                                 20.0   mg/ml                                        oil)                                                                          castor oil ad.            1.00   ml                                           ______________________________________                                    

EXAMPLE 5 Formulation of an eye gel

    ______________________________________                                        diclofenac potassium     0.50   mg/g                                          thiomersal               0.04   mg/g                                          boric acid               1.8    mg/g                                          cremophor EL ® (polyoxyl 35 castor oil)                                                            4.0    mg/g                                          tromethamine             13.0   mg/g                                          carbomer 980             4.0    mg/g                                          deion. water ad.         1.00   g                                             ______________________________________                                    

EXAMPLE 6 Formulation of an eye gel

    ______________________________________                                        diclofenac potassium  1.00   mg/g                                             benzalkonium chloride 0.1    mg/g                                             tyloxapol             1.0    mg/g                                             mannitol              30.0   mg/g                                             hydrochloric acid 10% 1.0    mg/g                                             disodium edetate      0.5    mg/g                                             chitosan              10.0   mg/g                                             deion. water ad.      1.00   g                                                ______________________________________                                    

EXAMPLE 7 Formulation of an eye ointment

    ______________________________________                                        diclofenac potassium  1.00 mg/g                                               phenylethyl alcohol   5.0 mg/g                                                tyloxapol             1.0 mg/g                                                disodium edetate      0.5 mg/g                                                γ-cyclodextrin  20.0 mg/g                                               deion. water          140 mg/g                                                cetylstearyl alcohol  22.0 mg/g                                               liquid paraffin       207 mg/g                                                white petrolatum      462 mg/g                                                wool fat              141.5 mg/g                                              ______________________________________                                    

EXAMPLE 8 Formulation of diclofenac potassium eye drops (0.05%)

    ______________________________________                                        diclofenac potassium      0.5    mg/ml                                        cremophor RH ® (polyoxyl 40 hydrogenated castor oil)                                                0.6    mg/ml                                        tromethamine              1.0    mg/ml                                        disodium edetate          0.5    mg/ml                                        sorbitol                  49.0   mg/ml                                        benzalkonium chloride     0.15   mg/ml                                        hydrochloric acid 1N      5.1    mg/ml                                        water for injections ad   1.0    ml                                           pH                        7.53                                                osmolality (mOsmol):      317                                                 ______________________________________                                    

EXAMPLE 9 Formulation of diclofenac sodium eye drops (0.1%)

    ______________________________________                                        diclofenac sodium         1.0    mg/ml                                        cremophor RH ® (polyoxyl 40 hydrogenated castor oil)                                                0.6    mg/ml                                        tromethamine              1.0    mg/ml                                        disodium edetate          0.5    mg/ml                                        sorbitol                  49.0   mg/ml                                        benzalkonium chloride     0.15   mg/ml                                        hydrochloric acid 1N      5.52   mg/ml                                        water for injections ad   1.0    ml                                           pH                        7.49                                                osmolality (mOsmol):      308                                                 ______________________________________                                    

EXAMPLE 10 Formulation of an eye drop vehicle

    ______________________________________                                        cremophor RH ® (polyoxyl 40 hydrogenated castor oil)                                                0.6    mg/ml                                        tromethamine              1.0    mg/ml                                        disodium edetate          0.5    mg/ml                                        sorbitol                  49.0   mg/ml                                        benzalkonium chloride     0.15   mg/ml                                        hydrochloric acid 1N      5.0    mg/ml                                        water for injections ad   1.0    ml                                           pH:                       7.53                                                osmolality (mOsmol):      301                                                 ______________________________________                                    

EXAMPLE 11 Formulation of diclofenac potassium eye drops (0.1%)

    ______________________________________                                        diclofenac potassium      1.0    mg/ml                                        cremophor RH ® (polyoxyl 40 hydrogenated castor oil)                                                0.6    mg/ml                                        tromethamine              1.0    mg/ml                                        disodium edetate          0.5    mg/ml                                        sorbitol                  49.0   mg/ml                                        benzalkonium chloride     0.15   mg/ml                                        hydrochloric acid 1N      5.7    mg/ml                                        water for injections ad   1.0    ml                                           pH:                       7.35                                                osmolality (mOsmol):      314                                                 ______________________________________                                    

EXAMPLE 12

Changes in aqueous flares (expressed as the area under the kineticcurves (AUC)) for the arachidonic acid induced uveitis model, carriedout in pigmented rabbits.

The drugs listed infra (including placebo) are applied topically (30 μleach) to the left eye of pigmented rabbits (chinchilla pigmented femalerabbits) one hour before arachidonic acid instillations. Each oppositeeye is instilled for control with 30 μl of the vehicle formulation ofexample 10. Before the instillation of arachidonic acid, the animals areanesthetized with intramuscular injections of 35 mg/kg ketamine(Imalgene 1000®, Rhone Merieux) and 15 mg/kg xylazine (Rompun-Bayer).Arachidonic acid (0.5% aqueous solution, freshly prepared before use) isthen instilled into both eyes of the rabbits with a Hamilton syringe(twice 50 μl). A time interval of 5 minutes is kept between eachinstillation. The flares are then measured hourly, using an LCFM over atotal period of 6 hrs after the arachidonic acid challenge. Before eachmeasurement, the animals are freshly anesthetized with intramuscularinjections of 35 mg/kg ketamine (Imalgene 1000®, Rhone Merieux) and 15mg/kg xylazine (Rompun-Bayer), in order to completely immobilize theeyes. The LCFM method is similar to a slit lamp microscopy examination.The laser beam of a Kowa FC-1000 LCFM is scanning vertically within adistance of 0.6 mm towards the center of the anterior chamber. Eachmeasurement lasts about 0.5 seconds. Such a measurement is repeated fivetimes for each eye and the average of the photon counts is thencalculated and plotted versus the observation time, which lasts in total6 hours calculated from the induction of the inflammation. The resultsare summarized below, which show the integrated photon counts of thetreated and of the control eyes (AUC(treated) and AUC(control)),representing the overall degree of said induced inflammation over said 6hours. Accordingly a high AUC number represents a strong inflammation,whereas a low AUC number represents a low degree of inflammation.

The ratio, AUC(treated) divided by AUC(control), is calculated as well.A low ratio value represents a strong anti-inflammatory efficacy,whereas a ratio value of about 1 reflects the substantial absence of ananti-inflammatory effect.

    __________________________________________________________________________                AUC(t)reated                                                                          AUC(c)ontrol                                                                         Ratio AUC(t)/AUC(c)                                Drug        Mean ± SEM                                                                         Mean ± SEM                                                                        Mean ± SEM                                      __________________________________________________________________________    placebo group (Unilarm ®)                                                             1616 ± 130                                                                         1793 ± 171                                                                        0.93 ± 0.09                                     diclofenac potassium                                                                      99 ± 20                                                                            1043 ± 186                                                                         0.1 ± 0.02                                     Example 8                                                                     diclofenac sodium                                                                         558 ± 141                                                                          1462 ± 270                                                                        0.46 ± 0.12                                     Example 9                                                                     __________________________________________________________________________

The AUC(treated) values show the superior efficacy of diclofenacpotassium (example 8) in comparison to the efficacy of diclofenac sodium(example 9). The inflammation in the animal group receiving diclofenacpotassium is almost totally suppressed. Taking into account the factthat the drug concentration of diclofenac sodium (example 9) is twicethe concentration of diclofenac potassium (0.1% versus 0.05%),diclofenac potassium is considered to have more than five fold efficacyof diclofenac sodium.

EXAMPLE 13

Lens penetration and ocular distribution of diclofenac potassium anddiclofenac sodium were determined after multiple topical ocularadministration of corresponding 14-C labelled eye drop composition intothe conjunctival sac of the right eye of pigmented rabbits.

At 0.5, 1.5, 2 hours post-instillation, 5 animals for each time-pointand each treatment group were sacrificed and the radioactivity content(in ng-Eq/g of structure) in the cornea, aqueous humor, iris-ciliarybody, vitreous, whole blood and plasma was measured. At 2 hourspost-instillation, the left eyes were removed and the oculardistribution was measured by a standard scintillation beta countingmethod. The right lenses were used for autoradiography.

The areas under the curve (AUC: ng-Eq/g of structure versus time) werecalculated and statistically compared.

The results indicated that the ocular penetration of diclofenacpotassium is much superior in comparison to diclofenac sodium:

    ______________________________________                                        Example 8 14-C-diclofenac potassium                                           Sampling       AUC: (ng-Eq/g)                                                 time (hour)    Mean = 5    SEM                                                ______________________________________                                        0.5            58 978      19 724                                             1.5            34 385      3 669                                              2.0            23 114      4 093                                              ______________________________________                                    

    ______________________________________                                        Example 9 14-C-diclofenac sodium                                              Sampling       AUC: (ng-Eq/g)                                                 time (hour)    Mean = 5    SEM                                                ______________________________________                                        0.5            30 342      5 721                                              1.5            20 201      5 061                                              2.0            13 840      3 497                                              ______________________________________                                    

EXAMPLE 8 14-C-diclofenac potassium

    ______________________________________                                        AUC: (ng-Eq/g) * hour                                                         Mean = 5           SEM                                                        ______________________________________                                        61 056             9 131                                                      ______________________________________                                    

EXAMPLE 9 14-C-diclofenac sodium

    ______________________________________                                        AUC: (ng-Eq/g) * hour                                                         Mean = 5           SEM                                                        ______________________________________                                        33 782             3 826                                                      ______________________________________                                    

The highest concentration were found for both studied drugs in thecornea and in descending order in aqueous humor, iris-ciliary body andvitreous.

EXAMPLE 14 eye drop formulations

    ______________________________________                                        diclofenac potassium                                                                             1.00   mg      0.5  mg                                     tromethamine       1.00   mg      1.00 mg                                     propylene glycol   20.5   mg      20.5 mg                                     hydroxypropyl-γ-cyclodextrin                                                               20.0   mg      20.0 mg                                     disodium edetate   1.00   mg      1.00 mg                                     benzalkonium chloride                                                                            0.06   mg      0.06 mg                                     hydrochloric acid 1N                                                                             qs             qs                                          water for injections ad                                                                          1.00   ml      1.00 ml                                     pH                 7.90           7.90                                        osmolality (mOsmol)                                                                              296            296                                         preservative efficacy (Ph. Eur.)                                                                 A              A                                           ______________________________________                                    

The European Pharmacopoeia (Ph. Eur.) describes an efficacy test forantimicrobial preservation. Accordingly a preserved solution isinoculated with micro-organisms, characterized in that 10⁵ to 10⁶micro-organisms are contained in one milliliter of the challengedpreparation. The inoculum used does not exceed 1% of the total volume ofsaid preparation. Five micro-organisms are used for the challenge, eachseparately namely, pseudomonas aeruginosa, staphylococcus aureus,candida albicans and aspergillus niger. The challenged solutions arekept at room temperature and protected from light. At regular timeintervals samples are removed and the number of viable micro-organismsis determined either by plate count or by membrane filtration. Forophthalmic preparations the European Pharmacopoeia recommends criteria"A", which require e.g. that the bacterial micro-organisms are reducedby a factor of 1000, 24 hours after the challenge. Criteria "B" arestill acceptable according to the recommendations of the EuropeanPharmacopoeia, and require e.g. that the bacterial micro-organisms arereduced by a factor of 10, 24 hours after the challenge (for detailsrefer to the European Pharmacopoeia, 1994). Accordingly, whenever thepreservative efficacy recommendations of the European Pharmacopoeia arereferred to herein, this relates to the 1994 version.

EXAMPLE 15 diclofenac potassium eye drop formulations

    ______________________________________                                        diclofenac potassium                                                                             1.00   mg      0.5  mg                                     tyloxapol USP      1.00   mg      1.00 mg                                     tromethamine       1.00   mg      1.00 mg                                     propylene glycol   19.0   mg      19.0 mg                                     hydroxypropyl-γ-cyclodextrin                                                               20.0   mg      20.0 mg                                     disodium edetate   1.00   mg      1.00 mg                                     benzalkonium chloride                                                                            0.05   mg      0.05 mg                                     hydrochloric acid 1N                                                                             qs             qs                                          water for injections ad                                                                          1.00   ml      1.00 ml                                     pH                 7.96           7.98                                        osmolality (mOsmol)                                                                              305            303                                         ______________________________________                                    

EXAMPLE 16 eye gel formulation comprising diclofenac potassium

    ______________________________________                                        diclofenac potassium                                                                             1.00   mg      1.00 mg                                     tyloxapol USP      1.00   mg      1.00 mg                                     tromethamine       6.50   mg      6.50 mg                                     propylene glycol          19.0    mg                                          sorbitol           40.0   mg                                                  hydroxypropyl-γ-cyclodextrin                                                               20.0   mg      20.0 mg                                     disodium edetate   1.00   mg      1.00 mg                                     benzalkonium chloride                                                                            0.05   mg      0.05 mg                                     carbopol 980       3.50   mg      3.50 mg                                     water for injections ad                                                                          1.00   ml      1.00 ml                                     pH                 8.06           8.00                                        osmolality (mOsmol)                                                                              298            308                                         viscosity (mPa s)  450            380                                         ______________________________________                                    

EXAMPLE 17 eye drops SDU (single dose units, non-preserved)

    ______________________________________                                        diclofenac potassium                                                                             1.00   mg      0.5  mg                                     tyloxapol USP      1.00   mg      1.00 mg                                     tromethamine       1.00   mg      1.00 mg                                     propylene glycol   19.0   mg      19.0 mg                                     hydroxypropyl-γ-cyclodextrin                                                               20.0   mg      20.0 mg                                     disodium edetate   1.00   mg      1.00 mg                                     hydrochloric acid 1N                                                                             qs             qs                                          water for injections ad                                                                          1.00   ml      1.00 ml                                     pH                 7.95           7.98                                        osmolality (mOsmol)                                                                              301            300                                         ______________________________________                                    

EXAMPLE 18 preservative efficacy

    ______________________________________                                        diclofenac sodium  1.00 mg  1.00 mg  --                                       diclofenac potassium                                                                             --       --       1.00 mg                                  2-hydroxypropyl-β-cyclodextrin                                                              15.0 mg  20.0 mg  15.0 mg                                  2-hydroxyethyl-β-cyclodextrin                                                               15.0 mg  20.0 mg  15.0 mg                                  hydroxypropyl-γ-cyclodextrin                                                               --       --       --                                       boric acid         13.0 mg  13.0 mg  13.0 mg                                  borax              8.6 mg   8.6 mg   8.6 mg                                   methylparabene     0.26 mg  0.26 mg  0.26 mg                                  propylparabene     0.14 mg  0.14 mg  0.14 mg                                  sodium hydroxide 0.1 N                                                                           8.0 mg   6.0 mg   --                                       water for injections ad                                                                          1.0 ml   1.0 ml   1.0 ml                                   pH:                7.80     7.86     7.89                                     Osmolality (mOsmol)                                                                              332      325      308                                      preservative efficacy Ph. Eur.                                                                   r.n.m.   r.n.m.   r.n.m.                                   ______________________________________                                    

r.n.m.(recommendations not met), the preservative efficacy of thecorresponding composition does not meet the recommendations of theEuropean Pharmacopoeia.

EXAMPLE 19 preservative efficacy

    ______________________________________                                        diclofenac sodium --       --       1.00 mg                                   diclofenac potassium                                                                            1.00 mg  1.00 mg  --                                        2-hydroxypropyl-β-cyclodextrin                                                             20.0 mg  --       --                                        2-hydroxyethyl-β-cyclodextrin                                                              20.0 mg  --       --                                        hydroxypropyl-γ-cyclodextrin                                                              --       20.0 mg  20.0 mg                                   boric acid        13.0 mg  13.0 mg  13.0 mg                                   borax             8.6 mg   8.6 mg   8.6 mg                                    methylparabene    0.26 mg  0.26 mg  0.26 mg                                   propylparabene    0.14 mg  0.14 mg  0.14 mg                                   sodium hydroxide 0.1 N                                                                          2.0 mg   0.3 mg   0.4 mg                                    water for injections ad                                                                         1.0 ml   1.0 ml   1.0 ml                                    pH: (8 ± 0.3)  7.90     7.89     7.92                                      Osmolality (mOsmol), (300 ± 30)                                                              323      288      285                                       preservative efficacy Ph. Eur.                                                                  r.n.m.   r.n.m.   r.n.m.                                    ______________________________________                                    

What is claimed is:
 1. A method for treating glaucoma which isassociated with administered or endogenous glucocortioids, said methodcomprising the step of administering a therapeutically effective amountof an ophthalmic composition comprising diclofenac potassium and acarrier.
 2. The method of claim 1 wherein said ophthalmic compositionfurther comprises a stabilizer.
 3. The method of claim 2 wherein saidstabilizer is selected from the group consisting of vitamin E, vitamin Ederivatives and mixtures thereof.
 4. The method of claim 1 wherein saidophthalmic composition further comprises a solubilizer.
 5. The method ofclaim 2 wherein said stabilizer is a cyclodextrin.
 6. The method ofclaim 1 wherein said ophthalmic composition comprises from 0.000001 to5% by weight of diclofenac potassium.
 7. The method of claim 1 whereinsaid ophthalmic composition comprises from 0.001 to 1% by weight ofdiclofenac potassium.